Warfarin, a Comprehensive Review by Jay Patel – Presentation.Pdf
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Warfarin: A Comprehensive Review Jay M Patel, PharmD Objectives • Explain the important pharmacodynamic and pharmacokinetic properties of warfarin • Describe the role of warfarin in the inpatient setting • Identify factors that may contribute to variability in the INR with warfarin use • Discuss warfarin initiation and dose adjustments based on a comprehensive review of the patient Disclaimer Dr. Patel has no actual or potential conflict of interest associated with this presentation Coumadin® (Warfarin) • Clinical Pharmacology – Inhibit synthesis of Vitamin K dependent clotting factors • II, VII, IX and X • Protein C and S • Mechanism of Action – “Vitamin K antagonist” (VKA) – Inhibit C1 subunit of vitamin K epoxide reductase (VKORC1) enzyme complex Coumadin® (Warfarin) • Elimination half-lives of vitamin K- dependent proteins Factor Half-Life II 42-72 hours VII 4-6 hours IX 21-30 hours X 27-48 hours Protein C 8 hours Protein S 60 hours Clotting Cascade.http://medlibes.com/uploads/Screen%20shot%202010-07-30%20at%2012.56.57%20PM.png. Accessed May 15, 2015. Warfarin Response. El Camino Hospital. http://elcaminogmi.dnadirect.com/img/content/tests/drug_response/howWarfarinAffectsBloodClotting.gif. Date Accessed May 14, 2015. Accessed May 14, 2015 Question 1 • Warfarin, through the inhibition of VKOR, inhibits the production of which factors? A. II, VIII, XII, Protein C and Protein S B. I, II, III, and X C. XI, Protein C and Protein S D. II, VII, IX, X, Protein C and Protein S Pharmacokinetics • Racemic mixture of R- and S- enantiomers – S- 2 to 5 times more anticoagulant activity • Completely absorbed after oral administration • Small volume of distribution – ~0.14 L/Kg Pharmacokinetics • Approximately 99% protein bound • Extensive hepatic metabolization – CYP2C9, 2C19, 2C8, 2C18, 1A2 and 3A4 • S- enantiomer 2C9 • R- enantiomer 1A2/3A4 – Minimally active metabolites excreted mainly in urine and lesser extent in bile • Singe dose terminal half-life ~ 1 week • Effective half life 20-60 hours Question 2 • Which entantiomer is a more potent anticoagulant and is primarily metabolized by CYP2C9? A. R-enantiomer B. S-enantiomer Warfarin Initiation – CHADS2 Lamichhane, D. Update on secondary prevention of ischaemic stroke. http://jpma.org.pk/images/July2014/Update%20on%20secondary%20table2.jpg Published July, 2014. Accessed May 14, 2015. FDA Approved Indications • Prophylaxis and/or treatment of – Venous thrombosis and its extension, and pulmonary embolism – Thromboembolic complications associated with atrial fibrillation and/or cardiac valve replacement • Reduce risk of death, recurrent myocardial infarction (MI), and thromboembolic events such as stroke or systemic embolism after MI Other Uses of Warfarin • Orthopedic, general or urological surgery – Hip or knee arthroplasty – Hip fracture surgery – Abdominal or pelvic surgery – Prevention of transient ischemic attacks Warfarin Dosing Inpatient • Initiation overlap for heparin/low molecular weight heparin (LMWH) and VKA – Historically • Unfractionated heparin (UFH) 5-7 days then co- administer VKA – Contemporary practice • VKA therapy initiated day 1 or 2 UFH/LMWH Warfarin Dosing Inpatient • Initial dose selection – Doses should be individualized based on a comprehensive review of the patient – General recommendations • 5 mg daily for healthy individuals • 2.5mg daily for individuals with concomitant factors Patient Factors • Increased age • Diarrhea • Varying size • Thyroid disorders • Nutritional status • Hepatic/renal • Drug-drug dysfunction interactions • Genomic variants* • Chronic heart failure – CYP2C9 (*2 or *3 alleles) • Elevated baseline – VKORC1 INR polymorphism *The American College of Chest Physicians recommends against the use of routine pharmacogenomic testing to guide dosing Question 3 • Which of the following patient factors can influence initial warfarin dosing and INR variability? A. Age B. Diarrhea C. Nutritional status D. Chronic heart failure exacerbation E. All of the above Target INR • International normalized ratio (INR) – (Patient PT/Mean normal PT)ISI – ISI = International Sensitivity Index • Responsiveness of given thromboplastin to reduction of the vitamin K-dependent coagulation factors • More responsive agent low ISI Recommended Target INR Indication INR Duration Antiphospholipid Syndrome No additional risk factors 2 to 3 Indefinite Recurrent events with therapeutic INRs 2.5 to 3.5 Indefinite DVT and PE Transient/reversible risk factor 2 to 3 3 Months Unprovoked 2 to 3 3 Months Second episode unprovoked 2 to 3 Long-term With active cancer or LMWH for 3-6 months 2 to 3 Indefinite Atrial Fibrillation With prior CVA or TIA or systemic embolism 2 to 3 Long-term With mitral stenosis 2 to 3 Long-term Following open heart surgery 2 to 3 4 weeks PPX = prophylaxis; VT = venous thrombosis Recommended Target INR Indication INR Duration Mechanical Heart Valve Aortic bileaflet or tilting disk 2 to 3 Long-term Mitral bileaflet or tilting disk 2.5 to 3.5 Long-term Aortic or mitral caged ball or caged disk 2.5 to 3.5 Long-term Any valve with additional risk factor 2.5 to 3.5 Long-term Bioprosthetic Heart Valve Aortic N/A Aspirin 50-100mg Mitral 2 to 3 3 months W/ prior history of systemic embolism 2 to 3 3 months W/ left atrial thrombus 2 to 3 Until resolves Cardioembolic Ischemic Stroke 2 to 3 Long-term Factors Influencing INR Variability • Other medications – Antibiotics – CYP450 inducers/inhibitors • Diet • Increased/decreased activity • Increased/decreased weight Factors Influencing INR Variability • Antibiotics – Disrupt vitamin K-producing intestinal flora • Increased effect of warfarin • Inhibit metabolism of warfarin – Generally within one week Factors Influencing INR Variability • CYP450 Inducers • CYP450 Inhibitors – Rifampin – Antifungals – Phenobarbital – Macrolides – Phenytoin – Fluoroquinolones – Prednisone – Antiretrovirals – St. John’s Wort – Amiodarone – Ritonavir – Propafenone – Smoking – Isoniazid – Fluvastatin – Grapefruit Factors Influencing INR Variability • Other medications – Amiodarone – Ascorbic acid – Acetaminophen – Corticosteroids – Sucralfate – Statins Factors Influencing INR Variability • Foods high in vitamin K – Leafy, green vegetables • Kale • Spinach • Brussel sprouts • Asparagus • Basil • Malnutrition • Diet ordered in house – NPO Dose Adjustments Target INR Goal of 2 -3 Warfarin Increased Warfarin Day INR Value Sensitivity Starting Dose (mg) Starting Dose Day 1 5 mg < 1.5 2.5 mg 5 mg < 1.5 2.5 mg 2.5mg 1.5 – 1.9 1 – 1.5 mg Day 2 1 – 2.5 mg 2 – 2.5 0.5 – 1 mg 0 mg > 2.5 0 mg 5 – 10 mg < 1.5 2.5 – 5 mg 2.5 – 5 mg 1.5 – 1.9 1 – 2.5 mg Day 3 0 – 2.5 mg 2 – 3 0 – 1 mg 0 mg > 3 0 mg Dose Adjustments Warfarin Increased Warfarin Starting Dose INR Value Sensitivity Starting Dose 10 mg < 1.5 5 mg 5 – 7.5 mg 1.5 – 1.9 3 – 5 mg Day 4 0 – 5 mg 2 - 3 0 – 2.5 mg 0 mg > 3 0 mg 10 mg < 1.5 5 mg 7.5 – 10 mg 1.5 – 1.9 3 – 5 mg Day 5 0 – 5 mg 2 - 3 0 – 2.5 mg 0 mg > 3 0 mg 7.5 – 12.5 mg < 1.5 3 – 7.5 mg 5 – 10 mg 1.5 – 1.9 2.5 – 5 mg Day 6 0 – 7.5 mg 2 – 3 0 – 4 mg 0 mg > 3 0 mg Increased Bleeding Risk • Current antiplatelet • End stage renal therapy disease • Elevated PT • GI bleed w/in past 30 – Normal: 9.4 – 12.5 days seconds • Surgery w/in past 2 • Thrombocytopenia weeks – Platelet <75 K/uL • Intracranial bleed w/in • Significant hepatic past 30 days disease • Medications – Cirrhosis or total bilirubin >2.4 mg/dL • Alcohol abuse history Signs and Symptoms of Bleeding • Low hemoglobin/hematocrit • Blood in urine, stool, or sputum • Intracranial bleeding – Confusion – Weakness – Loss of vision • Lightheadedness • Weakness • Black, tarry stools • Bleeding gums • Severe abdominal pains Warfarin Reversal FFP = fresh frozen plasma, PCC = prothrombin complex concentrate Warfarin Reversal • Kcentra® (prothrombin complex concentrate) – Factors II, VII, IX, and X – Proteins C and S • Urgent reversal of acquired coagulation factor deficiency induced by Vitamin K Antagonist therapy in adults with: – Acute major bleeding – Need for an urgent surgery/invasive procedure Warfarin Reversal • Kcentra® Dosing – Administer with Vitamin K concurrently Pre-treatment INR 2 – <4 4 – 6 >6 Dose* of Kcentra (Units of Factor IX) 25 35 50 / kg body weight Maximum dose Not to exceed Not to exceed Not to exceed (units of Factor IX) 2500 3500 5000 * Dose based on actual potency as stated on the carton Pharmacy Resources • American College of Chest Physicians (CHEST Journal) • Pharmacy.uchc.edu – Inpatient collaborative practice protocol • Warfarindosing.org • Global RPh Conclusion Initial dose selection • Target INR • New start versus continuing maintenance • Drug, disease, dietary interactions • Laboratory findings – Hepatic/renal function – Nutritional status – PT/INR – Hemoglobin/hematocrit Case 1 • A 75 year old female patient is being bridged to warfarin therapy following a pulmonary embolism. She has a past medical history of hypothyroidism, type 2 diabetes, and hypertension. • Her baseline INR is 1.4. • Her renal and hepatic function are normal. Case 1 • Home Medication list – Lisinopril 5 mg QD – Levothyroxine 50 mcg QD – Metformin 500mg BID • Inpatient Medication List – Lisinopril 2.5mg QD – Insulin sliding scale Case 1 • What initial dose of warfarin would you recommend for this patient? A. 1 mg B. 2.5 mg C. 5 mg D. 7.5 mg E. 10 mg Case 1 • The medical team disagrees with your recommendation and gives the patient a 5 mg dose for 2 days. The INR is found to be 7.9 after the patient received the warfarin 5 mg. The patient has no evidence and is not expressing any symptoms of bleeding. Case 1 • The medical resident contacts you and asks what the next step should be regarding this patient’s therapy. What would you suggest? A. Administer 5 mg vitamin K PO B. Administer 5 mg vitamin K IV C. Hold warfarin until INR is therapeutic References • Ageno, et al. Oral Anticoagulant Therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines.